TY - JOUR T1 - A Critical, Nonlinear Threshold Dictates Bacterial Invasion and Initial Kinetics During Influenza JF - bioRxiv DO - 10.1101/052175 SP - 052175 AU - Amber M. Smith AU - Amanda P. Smith Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/05/08/052175.abstract N2 - Secondary bacterial infections increase morbidity and mortality of influenza A virus (IAV) infections. Bacteria are able to invade due to virus-induced depletion of alveolar macrophages (AMs), which are the host’s first line of defense. However, this is not the only factor contributing to bacterial invasion during IAV infection. By analyzing a theoretical model describing the coinfection kinetics, we uncovered nonlinear initial dose threshold that is dependent on the amount of AM depletion caused by the virus. This threshold separates a growth phenotype from a clearance phenotype such that bacteria initially decline for dose-AM depletion combinations below the threshold, stay constant for combinations near the threshold, and increase for combinations above the threshold. In addition, the distance from the threshold correlates to the growth rate. Because AM depletion changes throughout an IAV infection, the dose requirement for bacterial invasion will also change according to the threshold. Using the threshold calculation to estimate the dynamical dose requirement, we found that the dose requirement drops dramatically during the first 7d of the IAV infection. We then validated these analytical predictions experimentally by infecting mice with doses below or above the predicted threshold over the course of IAV infection. These results identify the nonlinear way in which two simultaneous, independent factors work together to support successful post-influenza bacterial invasion. They provide insight into the timing of coinfections, the heterogeneity in outcome, the probability of acquiring a coinfection, and the use of new therapeutic strategies to combat viral-bacterial coinfections. ER -